Ž .Brain Research 821 1999 218–223

Short communication

Ž .Chronic y deprenyl administration alters dendritic morphology of layer IIIpyramidal neurons in the prefrontal cortex of adult Bonnett monkeys

B.S. Shankaranarayana Rao, M.K. Lakshmana, B.L. Meti, T.R. Raju )

Department of Neurophysiology, National Institute of Mental Health and Neurosciences, P.B. a2900, Hosur Road, Bangalore 560 029, India

Accepted 15 December 1998

Abstract

Ž . Ž .Chronic y deprenyl 0.2 mgrkg, b.wt; for 25 days treatment induced alterations in the dendritic morphology of prefrontal corticalneurons in adult Bonnett monkeys were evaluated in the present study. The branching points and intersections in apical and basaldendrites were studied up to a distance of 400 and 200 mm, respectively, in Golgi impregnated layer III pyramidal neurons of the

Ž .prefrontal cortex. Our results revealed a significant p-0.001 increase in the number of branching points and intersections in bothŽ .apical and basal dendrites in y deprenyl treated monkeys compared to controls. Such an enriched dendritic arborization in prefrontal

Ž .cortical neurons may be responsible for the enhancement of cognitive functions in Alzheimer disease patients following y deprenyltreatment. q 1999 Elsevier Science B.V. All rights reserved.

Ž .Keywords: y Deprenyl; Monkey prefrontal cortex; Layer III pyramidal neuron; Dendritic arborization; Golgi staining; Neural plasticity

Ž . Ž .y Deprenyl selegiline , is a highly selective andŽ .irreversible inhibitor of monoamine oxidase B MAO-B

and widely used in the management of Parkinson’s andw x Ž .Alzheimer’s diseases 17,33 . In addition, y deprenyl is

w xeffective as an antidepressant 34 , neuroprotectant and aw x Ž .neurorescue agent 45 . y deprenyl has also been shown

w xto increase the life span of laboratory animals 24 . Re-Ž .cently, the specificity of y deprenyl as a cognitive

enhancer has been reported in both experimental animalsw xand humans 24,25,50 . Results from these studies haveŽ .revealed that y deprenyl might indirectly influence the

performance in cognitive tests through modulation of thecholinergic transmission in the mesolimbic systemw x Ž .24,25,50 . Since y deprenyl possesses cognitive en-hancing properties, it has also been introduced in the

w xtreatment of Alzheimer type dementia 35,50 . However,Ž .the mechanism by which y deprenyl improves cognitive

Ž .function in Alzheimer’s disease AD is not yet clearlyunderstood.

The mechanism involved in increasing the longevityŽ .and neuroprotection by y deprenyl is believed to be due

to an enhancement in the activity of free radical scaveng-

) Corresponding author. Fax: q91-80-6631830;E-mail: trraju@nimhans.kar.nic.in

w xing enzymes such as superoxide dismutase and catalase 5and also due to the diminished production of hydrogen

w xperoxide through MAO-B inhibition 7 . In addition to itsŽ .putative antioxidant properties, y deprenyl has been

w xshown to act as a trophic factor 21 and known to increasethe survival of hippocampal CA1 and spinal cord motorneurons in cerebral and spinal ischemia, respectivelyw x Ž .27,39 . y Deprenyl also enhances the neuritic out-

w xgrowth in cultured rat spinal ventral horn neurons 19 .AD leads to a progressive and irreversible loss of

memory and cognitive functions in affected individualsw x18 . Cholinergic system is strongly implicated in learning

w xand memory 10,49 and cholinergic dysfunction is thoughtw xto occur in AD 10 . Furthermore, AD is associated with

the reduction in dendritic branching pattern and synapticw xdensity in pyramidal neurons of the prefrontal cortex 8,46 .

Ž .Our previous studies have demonstrated the y deprenylinduced increase in the dendritic arborization in CA3neurons of the hippocampus and AChE activity in specificregions of the primate brain including the frontal cortexw x29 . However, there are no studies currently available on

Ž .the effect of y deprenyl on dendritic morphology in theprimate neocortical neurons. Accordingly, the present studywas carried out to evaluate alterations in the dendriticmorphology in layer III pyramidal neurons of the pre-

Ž .frontal cortex following chronic y deprenyl administra-tion in the monkey brain.

0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved.Ž .PII: S0006-8993 98 01362-6

( )B.S. Shankaranarayana Rao et al.rBrain Research 821 1999 218–223 219

Fig. 1. Schematic drawing of the lateral view of the Bonnett monkeyŽ .Macaca radiata brain showing the location of the cytoarchitectonic

Ž .region of the prefrontal cortex Walker’s area 46 examined in this study.Cross-hatched region demarcates the area, where neurons were selectedfor the Golgi study. AS, arcuate sulcus; CS, central sulcus; PS, principalsulcus.

ŽTwelve healthy adult male Bonnett monkeys Macaca.radiata used for the experiments were maintained in the

Primate Research Laboratory at the Indian Institute ofScience, Bangalore, India. All procedures related to themaintenance and use of these animals were in accordance

Ž .with the NIH guidelines. y Deprenyl was a gift from theŽ .International Pharmaceuticals, Ahmedabad, India. y De-

prenyl dissolved in physiological saline was administeredŽat a dose of 0.2 mgrkgrday i.m. which was similar to the

w x.dose used in our previous studies 28,29 for 25 daysŽ . Ž .ns6 . Control group of monkeys ns6 received intra-muscular injections of equimolar physiological saline.

After experimentation, monkeys were sacrificed underŽdeep anaesthesia Ketamine hydrochloride, 25 mgrkg b.wt,

.i.m. and medial prefrontal cortex was dissected and pro-cessed for rapid Golgi staining technique as described in

w xour earlier studies 29,43 . Coronal sections of 160 mmthickness were cut using a sledge microtome. Sectionswere collected serially, dehydrated in absolute alcohol,cleared in xylene, and coverslipped. Slides were codedprior to the quantitative analysis and the coding wasbroken only after the analysis was completed. The den-dritic branching points, intersections and total number ofdendrites were quantified from layer III pyramidal neuronsof the prefrontal cortex.

The middle frontal gyrus of the prefrontal cortex thatw xcontains Walker’s area 46 48 as indicated in Fig. 1 was

examined. Neurons were viewed randomly and only thoseneurons which fulfilled the following criteria were selected

Ž .for analysis: i pyramidal neurons must be located inmid-layer III, with apical dendrites projecting to layer I

Ž .and basilar dendritic tree confined to layer III, ii neuronsmust be dark and consistently sliver impregnated through-

Ž . Ž . Ž . Ž .Fig. 2. Golgi-impregnated layer III prefrontal cortical pyramidal neurons of vehicle- saline A and y deprenyl- B treated monkeys. Note morenumber of dendrites in B compared to A. Camera lucida tracings of these neurons are shown in Fig. 3. Scale bars40 mm.

( )B.S. Shankaranarayana Rao et al.rBrain Research 821 1999 218–223220

Ž .out the extent of all dendrites, iii dendrites must beŽ .untruncated and, iv stained neurons must be relatively

free from the neighboring impregnated neurons.Camera lucida tracings of 10 neurons from each animal

were made at 625= magnification, using a Leitz micro-scope. At the same magnification, concentric circles weredrawn on a tracing paper at 40 mm equivalent intervals,

Ž .with the aid of a stage micrometer Sholl’s analysis . Thenumber of dendritic branching points and intersectionswere counted in successive radial segments of 40 mmdistance, taking into consideration the center of the soma

w xas a reference point 29,43 . The points at which dendritescross the concentric circles were considered to be points ofintersection. Apical and basal dendrites were studied up toa distance of 400 and 200 mm, respectively. Ten neuronswere traced from each animal, accounting for 60 neuronsper group. The mean values were calculated for eachanimal, and these numbers were used as subjects for thestatistical analysis. The dendritic branching points andintersections data were subjected to two-way ANOVAwith repeated measures followed by Student’s t-test forintergroup comparisons. The data on total number of apicaland basal dendrites were analysed by Student’s t-test.

Ž .y Deprenyl treatment did not result in any change inŽ .food and water intake. The body and brain weights of y

deprenyl-treated monkeys were not significantly different

Fig. 4. Total number of branching points in apical and basal dendrites ofŽ .layer III pyramidal neurons of the prefrontal cortex from saline- S and

Ž . Ž .y deprenyl- D treated groups of monkeys. Note a significant increasein the number of branches in D compared to S in both apical and basaldendrites.

Ž . Ž . Ž .Fig. 3. Camera lucida tracings of the layer III frontal cortical pyramidal neurons from saline- A and y deprenyl- B treated monkeys depicted in Fig.2. Note an increase in both the number of dendritic branching points and dendritic length in the apical and basal dendritic tree of B compared to A. Scalebars40 mm.

( )B.S. Shankaranarayana Rao et al.rBrain Research 821 1999 218–223 221

Table 1Ž .Number of dendritic branching points and intersections in apical dendrites of layer III pyramidal neurons of prefrontal cortex in vehicle and y

deprenyl-treated monkeys

Ž .Segments 40 mm Branching points Intersections

Ž . Ž .Vehicle y Deprenyl Vehicle y Deprenyl

I 1.80"0.67 3.25"0.52) 1.80"0.67 3.25"0.52))

II 3.70"0.50 5.70"0.76))) 5.35"1.13 7.85"0.85))

III 1.65"0.41 4.70"0.82)))) 3.87"1.17 9.75"1.34)))

IV 1.25"0.71 3.80"0.63))) 2.60"1.11 6.45"0.70))))

V 0.75"0.25 3.35"0.44)))) 1.95"0.66 4.95"0.80))))

VI 0.95"0.44 2.15"0.41)) 1.75"0.52 3.55"0.34))))

VII 0.80"0.16 1.75"0.57) 1.85"0.47 3.50"0.52)))

VIII 0.45"0.10 0.95"0.52 1.87"0.28 2.85"0.19))))

IX 0.30"0.25 0.80"0.40 1.45"0.34 2.35"0.28))))

X 0.60"0.32 0.60"0.42 1.65"0.61 1.95"0.40

Ž .Values represent mean "S.D. data of 60 neurons in each group.Ž .) p-0.05; )) p-0.025; ))) p-0.01; )))) p-0.005 Student’s t-test .

from those of control animals. When data on apical den-dritic branching points were subjected to ANOVA withrepeated measures, a significant effect between groupsŽ . ŽF s37.84, p-0.001 and segments F s8.84, p1,10 9,90

.-0.001 was revealed. Comparisons made using Student’st-test showed a significant increase in the number of

Ž . Ž .dendritic branching points in I p-0.05 , II p-0.01 ,Ž . Ž . Ž . ŽIII p-0.005 , IV p-0.01 , V p-0.005 , VI p-. Ž .0.025 and VII p-0.05 segments, of apical dendrites in

Ž .y deprenyl-administered monkeys compared to controlsŽ .Figs. 2–4, Table 1 .

Statistical analysis of number of intersections in apicaldendrites also showed a significant effect between groupsŽ . ŽF s57.48, p-0.001 and segments F s26.93,1,10 9,90

.p-0.001 . There was an increase in the number of inter-Ž . Ž . Ž .sections in I p-0.025 , II p-0.025 , III p-0.01 ,

Ž . Ž . Ž . ŽIV p-0.005 , V p-0.005 , VI p-0.005 , VII p-. Ž . Ž0.01 , VIII and IX p-0.005 segments covering a

. Ž .distance of 360 mm of the y deprenyl-treated group ofŽanimals compared to the control group Figs. 2 and 3,

.Table 1 .Data on basal dendritic branching points and intersec-

tions when subjected to ANOVA also revealed a signifi-

Žcant effect between groups F s28.50, p-0.001 and1,10. ŽF s117.02, p-0.001 and segments F s6.89, p1,10 4,10

.-0.001 and F s5.00, p-0.002 . The number of4,10

branching points of basal dendrites were increased in IŽ . Ž . Ž . Ž .p-0.05 , II p-0.005 , III p-0.025 , IV p-0.05

Ž . Ž .and V p-0.05 segments in y deprenyl-treated groupcompared to the control. The number of dendritic intersec-

Ž . Ž .tions in I p-0.025 , II p-0.025 , III, IV and VŽ . Ž .P-0.001 segments in y deprenyl-administered mon-

Žkeys were increased compared to the control animals Figs..2–4, Table 2 . In addition, there was a significant increase

Ž .p-0.001 in the total number of apical and basal den-Ž . Ž .drites in y deprenyl-treated monkeys Table 3 .

The present study has demonstrated a significant in-crease in the dendritic branching points and intersectionsof pyramidal neurons of the prefrontal cortex. Recently,we reported an increase in the dendritic arborization inCA3 pyramidal neurons of the hippocampus induced byŽ . w x Ž .y deprenyl 29 . It has also been shown that chronic ydeprenyl treatment increases AChE activity in the frontal

w x Ž .cortex 29 . Thus, y deprenyl induced increase in theAChE activity might be one of the reasons for enhanceddendritic length and branching, in the prefrontal cortex,

Table 2Ž .Number of dendritic branching points and intersections in basal dendrites of layer III pyramidal neurons of the prefrontal cortex in vehicle and y

deprenyl-treated monkeys

Ž .Segments 40 mm

I II III IV V

( )I Branching pointsŽ .a Vehicle 8.15"1.39 2.50"0.80 0.35"0.25 0.10"0.16 0.0"0.0Ž . Ž .b y Deprenyl 11.90"1.40) 5.80"0.93))) 1.15"0.35)) 0.56"0.17)) 0.18"0.23)

( )II IntersectionsŽ .a Vehicle 8.15"1.39 10.35"0.66 7.50"0.88 1.85"0.70 0.10"0.20Ž . Ž .b y Deprenyl 11.90"1.40) 14.50"1.66)) 13.20"1.24)))) 6.30"0.73)))) 2.40"0.51))))

Ž .Values represent mean "S.D. data of 60 neurons from 6 monkeys in each group.Ž .) p-0.05; )) p-0.025; ))) p-0.005; )))) p-0.001 Student’s t-test .

( )B.S. Shankaranarayana Rao et al.rBrain Research 821 1999 218–223222

Table 3Ž .Total number of apical and basal dendrites in vehicle and y deprenyl-

treated groups of monkeys

Apical dendrites Basal dendrites

Ž . Ž .Vehicle y Deprenyl Vehicle y Deprenyl

1 14.6 17.8 10.0 16.02 10.0 17.6 11.8 14.03 11.0 23.4 12.0 14.64 14.4 23.9 11.0 15.85 11.0 19.4 10.0 16.66 12.8 19.6 11.0 17.1

Mean"S.D. 12.30"1.92 20.28"2.73) 10.96"0.85 15.68"1.80)

Values represent mean data of 10 neurons per animal.Ž .Student’s t-test comparison between vehicle and y deprenyl-treated

group: ) p-0.0001.

since AChE is known to regulate the neuritic outgrowthw x31,32,44 , and it has a morphogenic and axogenic role in

w xthe developing nervous system 40,41 . In addition, acetyl-w xcholine is also known to enhance neuritic outgrowth 32

w xand in tuning of the nerve growth cones 51 . Recently,AChE has been shown to induce long-term potentiationw x2 , suggesting that AChE may directly enhance cognitive

Ž .functions. The reported cognitive enhancing effect of yw xdeprenyl may be due to increased AChE activity 1,29,33

w xand enhanced dendritic arborization in hippocampal 29and prefrontal cortical neurons as observed in the presentstudy.

Ž .It is possible that metabolites of y deprenyl may alsoplay a role in altering the dendritic morphology. Dawirs et

w xal. 9 have shown a significant increase in the density ofspines in the prefrontal cortical neurons of gerbils by the

Ž .administration of a single dose of y deprenyl metabolite,w xmethamphetamine. In addition, haloperidol 23 and aging

w x47 is also known to induce synaptic alternations in theprefrontal cortical neurons. Our recent studies have shown

Ž .that chronic y deprenyl administration increases thew xdopamine metabolism in monkey prefrontal cortex 28 .

Such an increase in dopamine was also observed followingŽ .y deprenyl treatment in patients suffering from Parkin-

w xson’s disease 17,45 . It has been shown that the stimula-tion of the dopaminergic system increases cerebral blood

Ž .flow CBF in animals and in humans either on a global orw xregional level 11,12,15,20 . Most of the studies have been

performed with the dopaminergic agonists like apomor-phine and piribedil which produce an increase in the CBF,oxygen consumption and glucose uptake in different re-

w xgions of the brain including frontal cortex 36,37 , whereas,administration of pimozide, a putative dopaminergic antag-

w x w xonist prevents these effects 37 . McCulloch et al. 38showed that administration of apomorphine in rats in-creases regional CBF and glucose utilization in corticaland subcortical brain regions. In addition, L-DOPA treat-ment in Parkinson’s patients is known to increase CBF in

w x w xstriatum and neocortical regions 30 . Bes et al. 3 have

also found an increase of CBF particularly in the frontalcortex after bromocriptine administration in the patients ofPD. Thus, taken together, these results and our recent

Ž .finding of y deprenyl induced increased dopaminergicw xmetabolism in the frontal cortex 28 . It could be suggested

that deprenyl may bring about the observed increase indendritic arborization in the prefrontal cortical neurons byincreasing the cerebral metabolism.

Ž .Recent studies have shown that y deprenyl inducesŽ .the expression of nerve growth factor NGF and ciliary

Ž . w xneurotrophic factor CNTF genes in in vitro 13,42 .Neurotrophic factors play an important role in the plastic-ity of the central nervous system. For example, NGF canstimulate neuritic growth in a wide variety of cells includ-

w xing cholinergic 16,24 as well as cortical pyramidal neu-w xrons 26 . NGF also induces synaptogenesis, hypertrophy

w xof cortical cholinergic terminals 14 and long-lasting en-w xhancement of synaptic transmission 22 . In addition,

chronic intraventricular injection of NGF was found toelevate hippocampal choline acetyltransferase activity in

w xadult rats 16 and known to promote terminal growth inw xbasal forebrain cholinergic neurons 4,6 which could, in

turn, stimulate growth in cortical pyramidal neurons. TheŽ .treatment with y deprenyl may be beneficial in combat-

ing cortical dendritic atrophy in AD, leading to the recov-ery of cognitive functions.

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